PROJECT SUMMARY/ABSTRACT Since I launched my independent research program in 2013, we have focused at the intersection of mechanics and biomedicine. Specifically, I am interested in the mechanobiological feedback loop between cells and matrix mechanics wherein mechanical properties of matrix drive cell behavior which in turn modify tissue-level matrix properties. I have long been interested in the effects of the mechanical microenvironment on cell function, but the focus of my independent work has shifted to stromal cells and fibrosis. Fibrosis accompanies many acute and chronic diseases and is the cause of >40% of deaths in the U.S. Fibrotic processes often increase the effective stiffness of tissue in addition to traditional histological metrics. My vision for is to build model systems of mammalian regeneration, to identify mechanisms of cell contractility, and to target downstream effectors that control fibroproliferative cell function. To accomplish these goals, I am leveraging a novel model of mammalian regeneration, the African Spiny Mouse. The African Spiny Mouse (Acomys) can regenerate normal matrix after injury, with minimal scar tissue after many types of trauma, including full-thickness cuts, burns, myocardial infarction, spinal cord injury, and muscle necrosis. Unfortunately, what enables this adult mouse?s with this remarkable ability to regenerate normal matrix is currently poorly understood. The Maximizing Investigators? Research Award will enable me and my collaborators to determine the mechanisms of normal matrix regeneration in Acomys. My specific five-year goals are to (i) utilize engineered in vitro platforms to identify Rho GTPase pathways that may be altered in Acomys and leverage those mechanisms to minimize fibrosis in normal fibroblasts; (ii) utilize immunocompromised mice that have been transplanted with Acomys cells or tissues to investigate recruitment and activation of macrophages to sites of injury/regeneration; and (iii) create Acomys induced pluripotent stem cells for future use as in vitro and chimeric animal model systems. To complement these research objectives, I will continue teaching, mentoring, professional service, and community engagement to promote research and translation at the intersection of engineering and biomedicine.